Bupropion is used as an antidepressant. It has also been used either alone or in combination with other drugs as a smoking cessation aid. Bupropion is highly hygroscopic and susceptible to decomposition. Various techniques have been employed to overcome the stability issues with bupropion. These techniques have included combining bupropion hydrochloride with a stabilizing agent, typically a pharmaceutically acceptable acid, e.g., hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, malic acid, citric acid, tartaric acid, ascorbic acid, isoascorbic acid, etc. Other attempts to stabilize bupropion hydrochloride in pharmaceutical dosage forms include application of coating films or barriers, either on the bupropion hydrochloride or on excipients utilized in preparation of bupropion hydrochloride pharmaceutical dosage forms. It has also been proposed to stabilize bupropion hydrochloride in pharmaceutical dosage forms by forming complexes between the bupropion hydrochloride and an ion exchange resin, or by occluding the bupropion hydrochloride with cyclodextrin. Others have reported that bupropion hydrochloride is stable by itself under normal storage conditions, but can easily degrade in the presence of conventional excipients used in commercial formulations. It has been theorized that small amounts of impurities in the excipients, typically residual impurities such as peroxides, superoxides, hypochlorites and formic acid introduced during the manufacturing processes, can interact with the bupropion hydrochloride to cause decomposition during storage. Accordingly, it has been proposed that one possible strategy to eliminate or reduce decomposition of bupropion hydrochloride in pharmaceutical dosage forms is to pretreat the excipients to remove or neutralize impurities that can induce oxidation, add chelating agents to formulations to prevent metal induced oxidation, and/or add antioxidants such as L-cysteine hydrochloride to pharmaceutical dosage forms containing bupropion hydrochloride.
Commercially available sustained-release oral formulations of bupropion hydrochloride have been prepared by mixing the bupropion hydrochloride with a stabilizing agent and with various celluloses, alkyl celluloses and hydroxyalkylcelluloses, carboxyalkylcelluloses, polyalkylene glycols and acrylic acid polymers. It has also been proposed that complexes formed between bupropion hydrochloride and an ion exchange resin may be used for achieving a sustained-released effect.
The utility of pharmaceutical therapies and compositions involving the combination of mecamylamine hydrochloride and bupropion hydrochloride in the treatment of tobacco addiction or nicotine addiction, for palliating nicotine withdrawal symptoms, and/or facilitating smoking sensation is disclosed in U.S. Pat. No. 6,197,827, which is incorporated by reference in its entirety herein. This patent generally describes the concept of administering mecamylamine and bupropion either individually or in a single tablet, but does not disclose any particular formulation, or provide details as to how stable sustained-release tablet formulations comprising a therapeutically effective combination of mecamylamine hydrochloride and bupropion hydrochloride can be prepared. There is only a relatively general suggestion that time-release formulations may be prepared “as is known in the art and disclosed in U.S. Pat. Nos. 4,690,825 and 5,005,300,” and that “conventional means with pharmaceutically acceptable excipients such as binding agents . . . ; fillers . . . ; disintegrants . . . ; or wetting agents . . . ; glidants, artificial and natural flavors and sweeteners; artificial or natural colors and dyes; and stabilizers” may be employed. This teaching does not recognize potential interactions between mecamylamine hydrochloride and bupropion hydrochloride, and does not address the known stability issues with bupropion hydrochloride.